This proposal will determine the mechanisms by which cannabinoids and their receptors regulate immune responses. We have previously shown that treatment with the major psychotropic component of marijuana, D9-tetrahydrocannabinol (THC), or an endocannbinoid analog, methanandamide, leads to increased tumor growth in immune competent mice. However, in immune deficient SCID mice THC has no effect on tumor progression. Consistent with CB2 receptor involvement in immune suppression, the THC mediated increased tumor progression was blocked by CB2 receptor antagonism. However, the increased rate of tumor progression observed in methanandamide treated mice was not blocked CB2 receptor antagonism. This suggests differences in the mechanisms whereby methanandamide and THC cause an increase in the rate of tumor growth. Thus, while THC administration impairs anti-tumor immunity by CB2 receptor dependent signaling, the mechanism by which methanandamide limits anti-tumor responses remains to be elucidated. Our latest preliminary results have shown that in contrast to treatment with THC or methanandamide, treatment with anandamide results in a reduction of tumor growth. In addition our preliminary results have shown that anandamide treatment induces apoptosis of murine tumor cells in vitro. This proposal will determine the mechanisms by which cannabinoid receptor ligands differentially modulate tumor growth. We will determine the role endocannabinoids play in regulating immune responses by following their effects on tumor progression, cytokine production, and regulation of COX-2 expression and activity. We will examine the role of the CB1 and CB2-cannabinoid receptors in immune regulation by the use of CB1/CB2 receptor specific ligands complemented by the use of CB1 and CB2 knockout mice. We will utilize both in vitro and in vivo assays to determine the ability of endocannabinoids and their COX-2metabolites to induce apoptosis. We hypothesize that cannabinoid mediated signaling can promote or inhibit tumorigenicity depending on the relative impact on apoptosis or immune suppression mediated by a particular ligand. This proposal will determine the function of endocannabinoid and cannabinoid regulation of immunity and apoptosis and will evaluate the roles of the CB1 and CB2 receptors in this regulation.